tbuckley/cabot-search huggingface dataset:
Preclinical development of 1B7/CD3, a novel anti-TSLPR bispecific antibody that targets CRLF2-rearranged Ph-like B-ALL
Authors: Ze Tian, Chunhua Shi, Guojun Yang, Jason K. Allen, Qing Shi, Amin AL-Shami, Jill Wardell Olson, Melinda G. Smith, Qing Chang, Jasbir Kaur, Junping You, Timothy E. Lofton, Michelle A. Gonzalez, Qi Zhang, DongXing Zha, Sarah K. Tasian, Nitin Jain, Marina Y. Konopleva, Timothy Heffernan, Jeffrey J. Molldrem
Journal: Leukemia (2023)

Abstract Patients harboring CRLF2 -rearranged B-lineage acute lymphocytic leukemia (B-ALL) face a 5-year survival rate as low as 20%. While significant gains have been made to position targeted therapies for B-ALL treatment, continued efforts are needed to develop therapeutic options with improved duration of response. Here, first we have demonstrated that patients with CRLF2 -rearranged Ph-like ALL harbor elevated thymic stromal lymphopoietin receptor (TSLPR) expression, which is comparable with CD19. Then we present and evaluate the anti-tumor characteristics of 1B7/CD3, a novel CD3-redirecting bispecific antibody (BsAb) that co-targets TSLPR. In vitro, 1B7/CD3 exhibits optimal binding to both human and cynomolgus CD3 and TSLPR. Further, 1B7/CD3 was shown to induce potent T cell activation and tumor lytic activity in both cell lines and primary B-ALL patient samples. Using humanized cell- or patient-derived xenograft models, 1B7/CD3 treatment was shown to trigger dose-dependent tumor remission or growth inhibition across donors as well as induce T cell activation and expansion. Pharmacokinetic studies in murine models revealed 1B7/CD3 to exhibit a prolonged half-life. Finally, toxicology studies using cynomolgus monkeys found that the maximum tolerated dose of 1B7/CD3 was ≤1 mg/kg. Overall, our preclinical data provide the framework for the clinical evaluation of 1B7/CD3 in patients with CRLF2 -rearranged B-ALL.
Outpatient Worsening Among Patients With Mildly Reduced and Preserved Ejection Fraction Heart Failure in the DELIVER Trial
Authors: Safia Chatur, Muthiah Vaduganathan, Brian L. Claggett, Jonathan W. Cunningham, Kieran F. Docherty, Akshay S. Desai, Pardeep S. Jhund, Rudolf A. de Boer, Adrian F. Hernandez, Silvio E. Inzucchi, Mikhail N. Kosiborod, Carolyn S.P. Lam, Felipe A. Martinez, Sanjiv J. Shah, Magnus Petersson, Anna Maria Langkilde, John J.V. McMurray, Scott D. Solomon
Journal: Circulation (2023)

Hospitalization is recognized as a sentinel event in the disease trajectory of patients with heart failure (HF), but not all patients experiencing clinical decompensation are ultimately hospitalized. Outpatient intensification of diuretics is common in response to symptoms of worsening HF, yet its prognostic and clinical relevance, specifically for patients with HF with mildly reduced or preserved ejection fraction, is uncertain.
Influence of background medical therapy on efficacy and safety of dapagliflozin in patients with heart failure with improved ejection fraction in the <scp>DELIVER</scp> trial
Authors: Maria Pabon, Brian L. Claggett, Xiaowen Wang, Zi Michael Miao, Safia Chatur, Ankeet S. Bhatt, Muthiah Vaduganathan, James C. Fang, Akshay S Desai, Pardeep Jhund, Felipe Martinez, Rudolf A. de Boer, Mikhail N. Kosiborod, Carolyn S.P. Lam, Sanjiv J. Shah, Adrian F. Hernandez, John J.V. McMurray, Scott D. Solomon, Orly Vardeny
Journal: European Journal of Heart Failure (2023)

The Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure (DELIVER) trial demonstrated the sodium-glucose cotransporter 2 inhibitor dapagliflozin to be beneficial in patients with symptomatic heart failure (HF) with improved ejection fraction (HFimpEF; those with prior left ventricular ejection fraction ≤40% that had improved to >40% by enrolment). Whether this benefit differs by background medical therapy is unclear. The current study aims to determine the efficacy and safety of dapagliflozin among patients with HFimpEF by background medical therapy.Treatment effects on the primary endpoint (worsening HF or cardiovascular death) were assessed by number of background HF medical therapies (angiotensin-converting enzyme inhibitor/angiotensin receptor blocker/angiotensin receptor-neprilysin inhibitor, evidence-based beta-blocker, and mineralocorticoid receptor antagonist). Among the 6263 patients randomized in DELIVER, 1151 (18%) had HFimpEF. Of those, 21% of patients were on 0-1 therapies, 44% were on two therapies, and 35% were on three therapies. During 2.3 years of median follow-up, the incidence rate of the primary outcome was 9.7, 8.8, and 8.4 per 100 person-years for patients on 0-1, 2 and 3 HF medications at baseline, respectively. Treatment effects with dapagliflozin on the primary outcome may be greater in patients with HFimpEF on 0-1 therapies at baseline (pinteraction = 0.09), driven mostly by a significant interaction for HF hospitalization (pinteraction = 0.023) with no evidence of effect modification for cardiovascular death (pinteraction = 0.65). Treatment effects of dapagliflozin on the primary outcome were, however, consistent when assessed across the modified Heart Failure Collaboratory Medical Therapy Score integrating both therapeutic use and dosing (pinteraction = 0.39). The use of dapagliflozin was not associated with changes in use or doses of background HF therapies, and among patients on three HF medications at baseline, the addition of dapagliflozin did not lead to higher adverse events.In patients with HFimpEF, the safety and efficacy of dapagliflozin were largely similar by background use and dosing of HF medical therapies. The benefit of dapagliflozin in reducing HF events tended to be greater in those patients on 0-1 medications at baseline. Among patients already on three HF medical therapies, the addition of dapagliflozin was safe without requiring de-escalation of other therapies.
Nano‐calcipotriol as a potent anti‐hepatic fibrosis agent
Authors: Yina Zhang, Liying Wang, Jiajia Shao, Yanning Liu, Yining Lu, Jing Yang, Siduo Xu, Jingkang Zhang, Minwei Li, Xiangrui Liu, Min Zheng
Journal: MedComm (2023)

Calcipotriol (CAL) has been widely studied as a fibrosis inhibitor and used to treat plaque psoriasis via transdermal administration. The clinical application of CAL to treat liver fibrosis is bottlenecked by its unsatisfactory pharmacokinetics, biodistribution, and side effects, such as hypercalcemia in patients. The exploration of CAL as a safe and effective antifibrotic agent remains a major challenge. Therefore, we rationally designed and synthesized a self-assembled drug nanoparticle encapsulating CAL in its internal hydrophobic core for systematic injection (termed NPs/CAL) and further investigated the beneficial effect of the nanomaterial on liver fibrosis. C57BL/6 mice were used as the animal model, and human hepatic stellate cell line LX-2 was used as the cellular model of hepatic fibrogenesis. Immunofluorescence staining, flow cytometry, western blotting, immunohistochemical staining, and in vitro imaging were used for evaluating the efficacy of NPs/CAL treatment. We found NPs/CAL can be quickly internalized in vitro, thus potently deactivating LX-2 cells. In addition, NPs/CAL improved blood circulation and the accumulation of CAL in liver tissue. Importantly, NPs/CAL strongly contributed to the remission of liver fibrosis without inducing hypercalcemia. Overall, our work identifies a promising paradigm for the development of nanomaterial-based agents for liver fibrosis therapy.
Hot and cold tumors: Immunological features and the therapeutic strategies
Authors: Lianjie Wang, Hui Geng, Yujie Liu, Lei Liu, Yanhua Chen, Fanchen Wu, Zhiyi Liu, Shiliang Ling, Yan Wang, Lihong Zhou
Journal: MedComm (2023)

Abstract The “hotness” or “coldness” of the tumors are determined by the information of the cancer cells themselves, tumor immune characteristics, tumor microenvironment, and signaling mechanisms, which are key factors affecting cancer patients’ clinical efficacy. The switch mechanism of “hotness” and “coldness” and its corresponding pathological characteristics and treatment strategies are the frontier and hot spot of tumor treatment. How to distinguish the “hotness” or “coldness” effectively and clarify the causes, microenvironment state, and characteristics are very important for the tumor response and efficacy treatments. Starting from the concept of hot and cold tumor, this review systematically summarized the molecular characteristics, influencing factors, and therapeutic strategies of “hot and cold tumors,” and analyzed the immunophenotypes, the tumor microenvironment, the signaling pathways, and the molecular markers that contribute to “hot and cold tumors” in details. Different therapeutic strategies for “cold and hot tumors” based on clinical efficacy were analyzed with drug targets and proteins for “cold and hot tumors.” Furthermore, this review combines the therapeutic strategies of different “hot and cold tumors” with traditional medicine and modern medicine, to provide a basis and guidance for clinical decision‐making of cancer treatment.
Sex differences in long‐term outcomes following acute heart failure hospitalization: Findings from the Get With The Guidelines‐Heart Failure registry
Authors: Neil Keshvani, Sonia Shah, Iyanuoluwa Ayodele, Karen Chiswell, Brooke Alhanti, Larry A. Allen, Stephen J. Greene, Clyde W. Yancy, Windy W. Alonso, Harriette GC Van Spall, Gregg C. Fonarow, Paul A. Heidenreich, Ambarish Pandey
Journal: European Journal of Heart Failure (2023)

Abstract Aims Sex differences in long‐term outcomes following hospitalization for heart failure (HF) across ejection fraction (EF) subtypes are not well described. In this study, we evaluated the risk of mortality and rehospitalization among males and females across the spectrum of EF over 5 years of follow‐up following an index HF hospitalization event. Methods and results Patients hospitalized with HF between 1 January 2006 and 31 December 2014 from the American Heart Association's Get With The Guidelines‐Heart Failure registry with available 5‐year follow‐up using Medicare Part A claims data were included. The association between sex and risk of mortality and readmission over a 5‐year follow‐up period for each HF subtype (HF with reduced EF [HFrEF, EF ≤40%], HF with mildly reduced EF [HFmrEF, EF 41–49%], and HF with preserved EF [HFpEF, EF &gt;50%]) was assessed using adjusted Cox models. The effect modification by the HF subtype for the association between sex and outcomes was assessed by including multiplicative interaction terms in the models. A total of 155 670 patients (median age: 81 years, 53.4% female) were included. Over 5‐year follow‐up, males and females had comparably poor survival post‐discharge; however, females (vs. males) had greater years of survival lost to HF compared with the median age‐ and sex‐matched US population (HFpEF: 17.0 vs. 14.6 years; HFrEF: 17.3 vs. 15.1 years; HFmrEF: 17.7 vs. 14.6 years for age group 65‐69 years). In adjusted analysis, females (vs. males) had a lower risk of 5‐year mortality (adjusted hazard ratio [aHR] 0.89, 95% confidence interval [CI] 0.87–0.90, p &lt; 0.0001), and the risk difference was most pronounced among patients with HFrEF (aHR 0.87, 95% CI 0.85–0.89; p interaction [sex*HF subtype] = 0.04). Females (vs. males) had a higher adjusted risk of HF readmission over 5‐year follow‐up (aHR 1.06, 95% CI 1.04–1.08, p &lt; 0.0001), with the risk difference most pronounced among patients with HFpEF (aHR 1.11, 95% CI 1.07–1.14; p interaction [sex*HF subtype] = 0.001). Conclusions While females (vs. males) had lower adjusted mortality, females experienced a significantly greater loss in survival time than the median age‐ and sex‐matched US population and had a greater risk of rehospitalization over 5 years following HF hospitalization.
Concomitant Coronary Atheroma Regression and Stabilization in Response to Lipid-Lowering Therapy
Authors: Flavio G. Biccirè, Jonas Häner, Sylvain Losdat, Yasushi Ueki, Hiroki Shibutani, Tatsuhiko Otsuka, Ryota Kakizaki, Thomas M. Hofbauer, Robert-Jan van Geuns, Stefan Stortecky, George C.M. Siontis, Sarah Bär, Jacob Lønborg, Dik Heg, Christoph Kaiser, David Spirk, Joost Daemen, Juan F. Iglesias, Stephan Windecker, Thomas Engstrøm, Irene Lang, Konstantinos C. Koskinas, Lorenz Räber
Journal: Journal of the American College of Cardiology (2023)
Chest Pain in Cancer Patients
Authors: Paolo Bima, Pedro Lopez-Ayala, Luca Koechlin, Jasper Boeddinghaus, Thomas Nestelberger, Bernhard Okamura, Tamar S. Muench-Gerber, Alessandra Sanzone, Daria Skolozubova, David Djurdjevic, Maria Rubini Gimenez, Karin Wildi, Oscar Miro, Gemma Martínez-Nadal, Francisco J. Martin-Sanchez, Michael Christ, Dagmar Keller, Bertil Lindahl, Evangelos Giannitsis, Christian Mueller
Journal: JACC CardioOncology (2023)

Little is known about patients with cancer presenting with acute chest discomfort to the emergency department (ED). The aim of this study was to assess the prevalence of acute myocardial infarction (AMI), outcomes, and the diagnostic utility of recommended diagnostic tools in this population. Patients presenting with chest pain to the ED were prospectively enrolled in an international multicenter diagnostic study with central adjudication. Cancer status was assessed prospectively and additional cancer details retrospectively. Findings were externally validated in an independent multicenter cohort. Among 8,267 patients, 711 (8.6%) had cancer. Patients with cancer had a higher burden of cardiovascular risk factors and pre-existing cardiac disease. Total length of stay in the ED (5.2 hours vs 4.3 hours) and hospitalization rate (49.8% vs 34.3%) were both increased in patients with cancer (P < 0.001 for both). Among 8,093 patients eligible for the AMI analyses, those with cancer more often had final diagnoses of AMI (184 of 686 with cancer [26.8%] vs 1,561 of 7,407 without cancer [21.1%]; P < 0.001). In patients with cancer, high-sensitivity cardiac troponin T (hs-cTnT) but not high sensitivity cardiac troponin I (hs-cTnI) concentration had lower diagnostic accuracy for non–ST-segment elevation myocardial infarction (for hs-cTnT, area under the curve: 0.89 [95% CI: 0.86-0.92] vs 0.94 [95% CI: 0.93-0.94] [P < 0.001]; for hs-cTnI, area under the curve: 0.93 [95% CI: 0.91-0.95] vs 0.95 [95% CI: 0.94-0.95] [P = 0.12]). In patients with cancer, the European Society of Cardiology 0/1-hour hs-cTnT and hs-cTnI algorithms maintained very high safety but had lower efficacy, with twice the number of patients remaining in the observe zone. Similar findings were obtained in the external validation cohort. Patients with cancer have a substantially higher prevalence of AMI as the cause of chest pain. Length of ED stay and hospitalization rates are increased. The diagnostic performance of hs-cTnT and the efficacy of both the European Society of Cardiology 0/1-hour hs-cTnT and hs-cTnI algorithms is reduced. (Advantageous Predictors of Acute Coronary Syndromes Evaluation [APACE] Study; NCT00470587)
DNA repair and antibody diversification: the 53BP1 paradigm
Authors: Eleni Kabrani, Tannishtha Saha, Michela Di Virgilio
Journal: Trends in Immunology (2023)

The DNA double-strand break (DSB) repair factor 53BP1 has long been implicated in V(D)J and class switch recombination (CSR) of mammalian lymphocyte receptors. However, the dissection of the underlying molecular activities is hampered by a paucity of studies [V(D)J] and plurality of phenotypes (CSR) associated with 53BP1 deficiency. Here, we revisit the currently accepted roles of 53BP1 in antibody diversification in view of the recent identification of its downstream effectors in DSB protection and latest advances in genome architecture. We propose that, in addition to end protection, 53BP1-mediated end-tethering stabilization is essential for CSR. Furthermore, we support a pre-DSB role during V(D)J recombination. Our perspective underscores the importance of evaluating repair of DSBs in relation to their dynamic architectural contexts.
Succinate in the tumor microenvironment affects tumor growth and modulates tumor associated macrophages
Authors: Sahil Inamdar, Abhirami P. Suresh, Joslyn L. Mangal, Nathan D. Ng, Alison Sundem, Hoda Shokrollahzadeh Behbahani, Thomas E. Rubino, Jordan R. Yaron, Taravat Khodaei, Matthew Green, Marion Curtis, Abhinav P. Acharya
Journal: Biomaterials (2023)
Stroke risk management in carotid atherosclerotic disease: a clinical consensus statement of the ESC Council on Stroke and the ESC Working Group on Aorta and Peripheral Vascular Diseases
Authors: Piotr Musialek, Leo H Bonati, Richard Bulbulia, Alison Halliday, Birgit Bock, Laura Capoccia, Hans-Henning Eckstein, Iris Q Grunwald, Peck Lin Lip, Andre Monteiro, Kosmas I Paraskevas, Anna Podlasek, Barbara Rantner, Kenneth Rosenfield, Adnan H Siddiqui, Henrik Sillesen, Isabelle Van Herzeele, Tomasz J Guzik, Lucia Mazzolai, Victor Aboyans, Gregory Y H Lip
Journal: Cardiovascular Research (2023)

Abstract Carotid atherosclerotic disease continues to be an important cause of stroke, often disabling or fatal. Such strokes could be largely prevented through optimal medical therapy and carotid revascularization. Advancements in discovery research and imaging along with evidence from recent pharmacology and interventional clinical trials and registries and the progress in acute stroke management have markedly expanded the knowledge base for clinical decisions in carotid stenosis. Nevertheless, there is variability in carotid-related stroke prevention and management strategies across medical specialities. Optimal patient care can be achieved by (i) establishing a unified knowledge foundation and (ii) fostering multi-specialty collaborative guidelines. The emergent Neuro-Vascular Team concept, mirroring the multi-disciplinary Heart Team, embraces diverse specializations, tailors personalized, stratified medicine approaches to individual patient needs, and integrates innovative imaging and risk-assessment biomarkers. Proposed approach integrates collaboration of multiple specialists central to carotid artery stenosis management such as neurology, stroke medicine, cardiology, angiology, ophthalmology, vascular surgery, endovascular interventions, neuroradiology, and neurosurgery. Moreover, patient education regarding current treatment options, their risks and advantages, is pivotal, promoting patient’s active role in clinical care decisions. This enables optimization of interventions ranging from lifestyle modification, carotid revascularization by stenting or endarterectomy, as well as pharmacological management including statins, novel lipid-lowering and antithrombotic strategies, and targeting inflammation and vascular dysfunction. This consensus document provides a harmonized multi-specialty approach to multi-morbidity prevention in carotid stenosis patients, based on comprehensive knowledge review, pinpointing research gaps in an evidence-based medicine approach. It aims to be a foundational tool for inter-disciplinary collaboration and prioritized patient-centric decision-making.
Genomics of deletion 7 and 7q in myeloid neoplasm: from pathogenic culprits to potential synthetic lethal therapeutic targets
Authors: Minako Mori, Yasuo Kubota, Arda Durmaz, Carmelo Gurnari, Charnise Goodings, Vera Adema, Ben Ponvilawan, Waled S. Bahaj, Tariq Kewan, Thomas LaFramboise, Manja Meggendorfer, Claudia Haferlach, John Barnard, Marcin Wlodarski, Valeria Visconte, Torsten Haferlach, Jaroslaw P. Maciejewski
Journal: Leukemia (2023)

Abstract Complete or partial deletions of chromosome 7 (-7/del7q) belong to the most frequent chromosomal abnormalities in myeloid neoplasm (MN) and are associated with a poor prognosis. The disease biology of -7/del7q and the genes responsible for the leukemogenic properties have not been completely elucidated. Chromosomal deletions may create clonal vulnerabilities due to haploinsufficient (HI) genes contained in the deleted regions. Therefore, HI genes are potential targets of synthetic lethal strategies. Through the most comprehensive multimodal analysis of more than 600 -7/del7q MN samples, we elucidated the disease biology and qualified a list of most consistently deleted and HI genes. Among them, 27 potentially synthetic lethal target genes were identified with the following properties: (i) unaffected genes by hemizygous/homozygous LOF mutations; (ii) prenatal lethality in knockout mice; and (iii) vulnerability of leukemia cells by CRISPR and shRNA knockout screens. In -7/del7q cells, we also identified 26 up or down-regulated genes mapping on other chromosomes as downstream pathways or compensation mechanisms. Our findings shed light on the pathogenesis of -7/del7q MNs, while 27 potential synthetic lethal target genes and 26 differential expressed genes allow for a therapeutic window of -7/del7q.
Ferric Carboxymaltose in Heart Failure with Iron Deficiency
Authors: Robert J. Mentz, Jyotsna Garg, Frank W. Rockhold, Javed Butler, Carmine G. De Pasquale, Justin A. Ezekowitz, Gregory D. Lewis, Eileen O’Meara, Piotr Ponikowski, Richard W. Troughton, Yee Weng Wong, Lilin She, Josephine Harrington, Robert Adamczyk, Nicole Blackman, Adrian F. Hernandez
Journal: New England Journal of Medicine (2023)

Ferric carboxymaltose therapy reduces symptoms and improves quality of life in patients who have heart failure with a reduced ejection fraction and iron deficiency. Additional evidence about the effects of ferric carboxymaltose on clinical events is needed. Download a PDF of the Research Summary. In this double-blind, randomized trial, we assigned ambulatory patients with heart failure, a left ventricular ejection fraction of 40% or less, and iron deficiency, in a 1:1 ratio, to receive intravenous ferric carboxymaltose or placebo, in addition to standard therapy for heart failure. Ferric carboxymaltose or placebo was given every 6 months as needed on the basis of iron indexes and hemoglobin levels. The primary outcome was a hierarchical composite of death within 12 months after randomization, hospitalizations for heart failure within 12 months after randomization, or change from baseline to 6 months in the 6-minute walk distance. The significance level was set at 0.01. We enrolled 3065 patients, of whom 1532 were randomly assigned to the ferric carboxymaltose group and 1533 to the placebo group. Death by month 12 occurred in 131 patients (8.6%) in the ferric carboxymaltose group and 158 (10.3%) in the placebo group; a total of 297 and 332 hospitalizations for heart failure, respectively, occurred by month 12; and the mean (±SD) change from baseline to 6 months in the 6-minute walk distance was 8±60 and 4±59 m, respectively (Wilcoxon–Mann–Whitney P=0.02; unmatched win ratio, 1.10; 99% confidence interval, 0.99 to 1.23). Repeated dosing of ferric carboxymaltose appeared to be safe with an acceptable adverse-event profile in the majority of patients. The number of patients with serious adverse events occurring during the treatment period was similar in the two groups (413 patients [27.0%] in the ferric carboxymaltose group and 401 [26.2%] in the placebo group). Among ambulatory patients who had heart failure with a reduced ejection fraction and iron deficiency, there was no apparent difference between ferric carboxymaltose and placebo with respect to the hierarchical composite of death, hospitalizations for heart failure, or 6-minute walk distance. (Funded by American Regent, a Daiichi Sankyo Group company; HEART-FID ClinicalTrials.gov number, NCT03037931.) QUICK TAKE VIDEO SUMMARYFerric Carboxymaltose in HF with Iron Deficiency 01:52
Event-free survival in patients with polycythemia vera treated with ropeginterferon alfa-2b versus best available treatment
Authors: Heinz Gisslinger, Christoph Klade, Pencho Georgiev, Dorota Krochmalczyk, Liana Gercheva-Kyuchukova, Miklos Egyed, Petr Dulicek, Arpad Illes, Halyna Pylypenko, Lylia Sivcheva, Jiří Mayer, Vera Yablokova, Kurt Krejcy, Victoria Empson, Hans C. Hasselbalch, Robert Kralovics, Jean-Jacques Kiladjian, Heinz Gisslinger, Jean-Jacques Kiladjian
Journal: Leukemia (2023)